Pathway to Pain Relief

By Jeanne Erdmann

People with osteoarthritis (OA) often live with pain that reaches into every part of their lives. Medications currently on the market don’t work in everyone, and many come with side effects that can be dangerous. For instance drugs such as NSAIDs only alleviate about 30 percent of the pain, leaving some treatment options for osteoarthritis (OA) inadequate. NSAIDs and opioids also bring the risk of serious side effects, such as ulcers, heart and kidney problems, or drowsiness and risk of addiction with opioids.

As of March 2012, researchers were investigating new ways to treat OA using biologic medications similar to those used in treating rheumatoid arthritis. One class of drugs called anti-NGFs attack chronic pain by preventing pain signals from reaching the brain. Anti-NGFs are being tested for many conditions such as nerve damage from diabetes, cancer pain and OA.

One of the anti-NGFs being studied is called tanezumab, an antibody designed to specifically block nerve growth factor (NGF), which acts as a master control switch for pain. NGF helps nerve cells grow and divide. In some circumstances though, NGF stops being such a good guy. For example, in the inflammatory environment of an arthritic joint, NGF turns neighborhood bully by goading nearby immune cells into overreacting to inflammation.

Such an action keeps pain messages going to the brain until pain turns chronic and can’t be easily stopped.

Tanezumab and similar drugs work by blocking NGF in the same way that anti-tumor necrosis factor therapies block pathways that lead to inflammation in rheumatoid arthritis.

“It’s the pathway itself that’s critical,” says Nancy Lane, MD, an arthritis expert at University of California-Davis, and part of a group of researchers who have been studying tanezumab. “The idea is to get more pain relief without side effects,” she says.

In 2010, however, the U.S. Food and Drug administration (FDA) asked Pfizer Inc. (tanezumab’s manufacturer) and other manufacturers of anti-NGFs to suspend clinical studies for OA, lower back pain and for nerve damage from diabetes. The request was made after participants in a Phase III osteoarthritis trial experienced joint failure. Some of those affected required hip replacement surgery.

Dr. Lane and others are hoping that tanezumab and its therapeutic cousins get a second chance. Because anti-NGF therapies work so specifically to block pain the side effects are few and the drug seems to be safe, she says.

On March 12, 2012, the FDA Arthritis Advisory Committee heard testimony from a panel of arthritis and pharmaceutical experts who discussed the risk of anti-NGFs when compared to the benefit of pain relief, and recommended that the FDA resume trials.

People with osteoarthritis (OA) often live with pain that reaches into every part of their lives. Medications currently on the market don’t work in everyone, and many come with side effects that can be dangerous. For instance drugs such as NSAIDs only alleviate about 30 percent of the pain, leaving some treatment options for osteoarthritis (OA) inadequate. NSAIDs and opioids also bring the risk of serious side effects, such as ulcers, heart and kidney problems, or drowsiness and risk of addiction with opioids.

As of March 2012, researchers were investigating new ways to treat OA using biologic medications similar to those used in treating rheumatoid arthritis. One class of drugs called anti-NGFs attack chronic pain by preventing pain signals from reaching the brain. Anti-NGFs are being tested for many conditions such as nerve damage from diabetes, cancer pain and OA.

One of the anti-NGFs being studied is called tanezumab, an antibody designed to specifically block nerve growth factor (NGF), which acts as a master control switch for pain. NGF helps nerve cells grow and divide. In some circumstances though, NGF stops being such a good guy. For example, in the inflammatory environment of an arthritic joint, NGF turns neighborhood bully by goading nearby immune cells into overreacting to inflammation.

Such an action keeps pain messages going to the brain until pain turns chronic and can’t be easily stopped.

Tanezumab and similar drugs work by blocking NGF in the same way that anti-tumor necrosis factor therapies block pathways that lead to inflammation in rheumatoid arthritis.

“It’s the pathway itself that’s critical,” says Nancy Lane, MD, an arthritis expert at University of California-Davis, and part of a group of researchers who have been studying tanezumab. “The idea is to get more pain relief without side effects,” she says.

In 2010, however, the U.S. Food and Drug administration (FDA) asked Pfizer Inc. (tanezumab’s manufacturer) and other manufacturers of anti-NGFs to suspend clinical studies for OA, lower back pain and for nerve damage from diabetes. The request was made after participants in a Phase III osteoarthritis trial experienced joint failure. Some of those affected required hip replacement surgery.

Dr. Lane and others are hoping that tanezumab and its therapeutic cousins get a second chance. Because anti-NGF therapies work so specifically to block pain the side effects are few and the drug seems to be safe, she says.

On March 12, 2012, the FDA Arthritis Advisory Committee heard testimony from a panel of arthritis and pharmaceutical experts who discussed the risk of anti-NGFs when compared to the benefit of pain relief, and recommended that the FDA resume trials.

Painful Truth

Pain signals travel to the brain through specialized nerves called nociceptors. These specialized nerves can be found body-wide, including joints, muscles and tendons.

Pain can be a helpful reminder to rest an injured joint. Say you are rushing around the house and bang your knee on the coffee table. Nociceptors detect damage to the tissue and send a message to the brain that says “ouch.”

Once the injury is healed, though, the pain should stop. With joints damaged from the inflammation connected to OA, the pain doesn’t stop, in part because nerve growth factor keeps pain signals on a one-way street to the brain.

Once that pathway is established, chronic pain becomes its own ailment (See “Why You Hurt,” in May/June Arthritis Today).

Richard Brasington MD, a rheumatologist at Washington University School of Medicine in St. Louis, Mo., says that chronic pain from conditions such as OA, rheumatoid arthritis and nerve damage from diabetes, changes the brain in a way that worsens how even mild pain is interpreted. So a hangnail could actually feel like a broken finger.

A Second Chance?

In 2006 and 2007, Dr. Lane and colleagues conducted a study to test whether tanezumab was safe and effective. The team enrolled 450 patients with moderate to severe knee OA and gave them either a placebo or one of five specific doses of tanezumab. Treatments were given on days one and 56. Pain relief was measured out to 16 weeks. Others took a placebo.

In those receiving tanezumab, pain was reduced by 45 to 65 percent. Dr. Lane says that's about double the pain relief that NSAIDs offer. The study was published in 2010 in the New England Journal of Medicine.

Dr. Lane and others are still waiting to hear from the FDA as to whether tanezumab clinical trials can resume, although she expects trials will indeed restart.

The Phase III clinical trial that was halted included people with advanced OA, some of whom had joints with osteonecrosis, a condition that occurs when the blood supply to the hips is disrupted causing tissue death.

Dr. Lane says that doctors see osteonecrosis less often as more people have hip replacement surgery before the condition can occur. She suspects that OA worsened in some people, because, with pain so much better, they were too active and damaged joints already on the edge of failing.

Dr. Lane explains that researchers still need to make certain that tanezumab does not interact with NSAIDs to worsen joints. Patients taking anti-NGF therapy would not need other aspirin-like drugs or opioids, she says.

If anti-NGF trials resume for OA, and the FDA eventually approves tanezumab, it will open the door for other therapies that block nerve growth factor.

“NGF is the tip of the iceberg for what we’ll be able to offer arthritis sufferers,” says Dr. Lane.